The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia

Abstract

The intricate balance between excitation and inhibition (E/I) in the brain plays a crucial role in normative information processing. Dysfunctions in the E/I balance have been implicated in various psychiatric disorders, including schizophrenia (SCZ). In particular, abnormalities in GABAergic signaling, specifically in parvalbumin (PV)-containing interneurons, have been consistently observed in SCZ pathophysiology. PV interneuron function is vital for maintaining an ideal E/I balance, and alterations in PV interneuron-mediated inhibition contribute to circuit deficits observed in SCZ, including hippocampus hyperactivity and midbrain dopamine system overdrive. While current antipsychotic medications primarily target D2 dopamine receptors and are effective primarily in treating positive symptoms, novel therapeutic strategies aiming to restore the E/I balance could potentially mitigate not only positive symptoms but also negative symptoms and cognitive deficits. This could involve, for instance, increasing the inhibitory drive onto excitatory neurons or decreasing the putative enhanced pyramidal neuron activity due to functional loss of PV interneurons. Compounds targeting the glycine site at glutamate NMDA receptors and muscarinic acetylcholine receptors on PV interneurons that can increase PV interneuron drive, as well as drugs that increase the postsynaptic action of GABA, such as positive allosteric modulators of α5-GABA-A receptors, and decrease glutamatergic output, such as mGluR2/3 agonists, represent promising approaches. Preventive strategies aiming at E/I balance also represent a path to reduce the risk of transitioning to SCZ in high-risk individuals. Therefore, compounds with novel mechanisms targeting E/I balance provide optimism for more effective and tailored interventions in the management of SCZ.

Keywords: Excitatory-inhibitory balance; PV interneuron; Schizophrenia.

Figure 1.

Excitatory-inhibitory (E/I) imbalance as a potential mechanism in SCZ pathophysiology. (A) In a healthy state, excitatory inputs activate fast-spiking PV interneurons, which govern gamma oscillation activity. The inhibitory drive from PV interneurons regulates pyramidal excitatory neurons (Pyr) that maintain an optimal E/I balance. (B) In SCZ, it is hypothesized that dysfunction in PV interneurons occurs due to decreased excitatory input drive, reduced PV expression, and NMDAR hypofunction within PV interneurons, which will synthesize and release less GABA. This combination of factors reduces the inhibitory drive to pyramidal neurons, leading to increased pyramidal excitability. Therefore, the E/I balance shifts towards a higher ratio of excitation to inhibition and disrupted gamma oscillations that underlie SCZ symptoms.

Figure 2.

Hippocampal circuit dysfunction contributes to SCZ symptoms. The E/I imbalance within the hippocampus disrupts rhythmic activity and increases the excitatory drive to the prefrontal cortex which is believed to underlie the cognitive symptoms in SCZ. Moreover, the dysrhythmic excitatory drive from the hippocampus to the basolateral amygdala and its consequent connectivity with the cingulate cortex is suggested to contribute to the negative symptoms of the disorder. The positive symptoms are proposed to be a result of a polysynaptic cascade originating from hippocampus hyperexcitability that leads to an increased excitatory drive to the ventral striatum, thereby elevating the GABAergic tone directed at the ventral pallidum. As a consequence, this decreases the GABAergic inhibition of the midbrain dopamine system. This culminates in heightened dopamine tone within the projections to the associative striatum which potentially leads to positive symptoms in SCZ.

Figure 3.

Possible pharmacological strategies to address E/I imbalance. A) mechanisms that increase PVI drive, thereby increasing inhibitory control upon pyramidal (Pyr) neurons. One strategy is to employ endogenous co-agonists at the NMDA receptor glycine site to increase PVI drive. mAChR 1 agonists, such as xanomeline, activate an intracellular mechanism that increases PVI neuronal excitability. mGluR5 positive allosteric modulators/agonist increase the NMDA function in PV interneurons. Kv3.1 modulators allow PVIs to recover their rapid firing capabilities, thus increasing inhibitory output onto Pyr neurons. B) α5-GABA-A receptors are susceptible to the action of selective positive allosteric modulators that enhance the effect of GABA at the orthosteric site of the receptor. C) Finally, an approach to decrease Pyr hyperactivity by activating group II metabotropic glutamate receptors (mGluR2/3) agonists may be effective. These receptors are located presynaptically and have an inhibitory influence on Pyr neurons, decreasing glutamatergic output. Adapted from (Gomes and Grace,2021) [271].